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载有 5-亚苄基噻唑烷-2,4-二酮衍生物 SKLB023 的混合胶束,用于有效治疗非酒精性脂肪性肝炎
Authors Li Y, Zhang T, Liu Q, Zhang J, Li R, Pu S, Wu T, Ma L, He J
Received 24 January 2019
Accepted for publication 3 May 2019
Published 28 May 2019 Volume 2019:14 Pages 3943—3953
DOI https://doi.org/10.2147/IJN.S202821
Checked for plagiarism Yes
Review by Single-blind
Peer reviewers approved by Dr Jiang Yang
Peer reviewer comments 2
Editor who approved publication: Dr Mian Wang
Background: SKLB023,
a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically
inhibits inducible nitric oxide synthase and shows promise for treating
non-alcoholic steatohepatitis (NASH). However, its poor water solubility and
low bioavailability limits its clinical use. Here the drug was loaded into
phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these
limitations.
Methods: PBMM/SKLB023
was developed using a simple co-precipitation method, and formulation
parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were
investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse
model of NASH induced by a diet deficient in methionine- and choline.
Results: PBMM/SKLB023
particles were 11.36±2.08 nm based on dynamic light scattering, and loading the
drug into micelles improved its water solubility 300-fold. PBMM/SKLB023
inhibited proliferation and activation of HSC-T6 cells more strongly than free
SKLB023. PBMM/SKLB023 showed longer mean retention time and higher
bioavailability than the free drug after intravenous injection in Wistar rats.
In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation,
inflammation, and fibrosis to a significantly greater extent than free SKLB023.
Conclusion: PBMM/SKLB023
shows therapeutic potential for treating NASH and liver fibrosis.
Keywords: phosphatidylcholine-bile
salt-mixed micelles, bioavailability, solubilizing efficiency, NASH